DESCRIPTION: (Principal Investigator's Abstract) The specific aims of this revised competitive renewal application are: (1) New methodology for Tetrahydrofuran Synthesis. We will further develop the (3+2) reactions of carbonyl compounds and allylsilanes of general structure 98 and 114, generated by the asymmetric allylboration reactions of a second aldehyde with the gamma-silylalylboronates or gamma-sily1alylboranes 97, 101, 112 and 113. This methodology has the potential to become an extremely general and highly stereoselective three component coupling method for synthesis of substituted tetrahydrofurans. (2) Synthetic Applications of the (3+2) Annulation Strategy for Tetrahydrofuran Synthesis. The (3+2) annulation reactions of aldehydes and functionalized allylsilanes will be applied to the synthesis of bullatacin, asimicin, and trilobacin, members of the Annonaceotus acetogenin family. Further extensions of the (3+2) methodology will be developed in connection with a synthesis of pectenotoxin II. (3) Synthesis of Angelmicin B. This work will focus on development of methods for stereocontrolled synthesis of the chiral biaryl unit, as well as further extensions of the allylsilane (3+2) annulation strategy for tetrahydrofuran synthesis, specifically use of the chiral cyclohexenylsilane 197 for synthesis of the key tricyclic enone 162. The angelmicin B synthesis also presents the opportunity for further exploration of our 2-iodo-glycosyl donor methodology for synthesis of 2-deoxyglycosides. (4) Second Generation Synthesis of Aureolic Acid Antibiotics: Mithramycin. We will develop a second generation synthesis of mithramycin starting from chromomycinone, the natural aglycone. This synthesis will illustrate the synthetic potential of the 2-iodo and 2-bromo glycosyl donor methodology, and define an efficient strategy for synthesis of semi-synthetic analogs with modified oligosaccharide units. (5) Synthesis of Aureolic Acid Analogs. Structurally simplified analogs 251, 252, 253 and/or 254 will be synthesized to define the structural requirements for maximal DNA binding and antitumor activity.